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GLOBAL DELETION OF MICRORNA-181A RESULTS IN ELEVATED BLOOD PRESSURE IN MICE

Head, G.1; Peterson, M.1; Jackson, K.1; Lim, K.1; Evans, R.2; Davern, P.1; Charchar, F.3; Marques, F.1

doi: 10.1097/01.hjh.0000539017.06651.23
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Objective: MicroRNA-181a (miR-181a) is down-regulated in both human hypertensive subjects and genetically hypertensive mice (BPH/2J). We have previously shown miR-181a can bind to and regulate renin mRNA levels. Therefore, it is proposed that miR-181a may exert post-transcriptional control over the renin-angiotensin system via up-regulation of renin expression, thus increasing blood pressure (BP).

Aims: To determine the role of the miR-181a1 gene in BP regulation and renin expression in CRISPR/Cas9 miR-181a-1 knock out (KO) mice.

Design and method: Twelve-week-old wild-type (WT,n = 6), BPH/2J (n = 6) and miR-181a1 heterozygous (n = 6) and homozygous (n = 8) KO mice were implanted with radio-telemetry probes to measure BP, heart rate and activity. The cardiovascular response to aversive stress, as well as angiotensin-converting enzyme (ACE) inhibition and ganglionic blockade were recorded. Renal renin mRNA and miR-181a expression were assessed using real-time PCR.

Results: Mean arterial pressure (MAP) was 8 mmHg higher in homozygous KO compared to WT mice during the active (P < 0.001) but not the inactive period (P = 0.22). Similarly, systolic BP was 7.2 mmHg greater in homozygous KO mice during the active period only (P = 0.02). However, diastolic BP was 13% greater in homozygous KO mice during the active period (mean difference 12.7 mmHg, P < 0.001) and 11% greater during the inactive period (mean difference 8.9 mmHg, P = 0.02), when compared to WT mice. Heterozygous KO mice had similar MAP, systolic and diastolic BP to WT mice (all P = 1.0). WT, homozygous or heterozygous KO mice showed no difference in the pressor response to aversive stress or depressor response to ACE inhibition and ganglionic blockade (active period). Compared to WT mice, miR-181a levels were 12-fold lower in homozygous KO mice (P < 0.001) and this was associated with higher renal renin expression (fold change +2.2, P = 0.06).

Conclusions: Homozygous KO mice have elevated BP which appears to be driven primarily by increased diastolic BP. We propose that the elevated BP seen in these mice is due to an increase in renin expression mediated by a lack of regulation by miR-181a. This microRNA may be a target for future therapies to lower BP.

1Baker Heart and Diabetes Institute, Melbourne, Australia

2Department of Physiology, Monash University, Melbourne, Australia

3Federation University, Ballarat, Australia

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